Insulin therapy for the treatment of diabetes has been used for decades. Insulin therapy usually involves administering several injections of insulin each day. Such therapy usually involves administration of a long-acting basal injection once or twice daily, and an injection of a fast-acting insulin at mealtime (i.e. prandial use). One of the key improvements in insulin therapy was the introduction of rapid-acting insulin analogues. However, even with the rapid-acting insulin analogues, peak insulin levels typically do not occur until 50 to 70 minutes following the injection.
Therefore insulin injections do not replicate the natural time-action profile of insulin. In particular, the natural spike of the first-phase insulin release in a person without diabetes results in blood insulin levels rising within several minutes of the entry into the blood of glucose from a meal. By contrast, injected insulin enters the blood only slowly, with peak insulin levels occurring within 80 to 100 minutes following the injection of regular human insulin.
Because the rapid-acting insulin analogues do not adequately mimic the first-phase insulin release, diabetics using insulin therapy continue to have inadequate levels of insulin present at the initiation of a meal, and too much insulin present between meals. This lag in insulin delivery can result in hyperglycemia early after meal onset.
Insulin possesses self-association properties, and its concentration represents a major factor of self-association. At high concentrations, especially in pharmaceutical formulations, insulin will self-associate into dimer, hexamer, dodecamer, and crystal. However, the physiologically active form of insulin is the monomer, which binds with the insulin receptor and triggers a biological response.
The rapidity of insulin action is dependent on how quickly the insulin is absorbed from the subcutaneous tissue. When regular human insulin is injected subcutaneously, the formulation is primarily composed of hexamers containing two zinc ions. Due to its size, the hexameric insulin has a lower rate of diffusion and consequently, the absorption rate is slower than for smaller species.
Located within the hexamer are two zinc atoms that stabilize the molecule towards chemical and physical degradation. Post injection, a concentration driven dynamic equilibrium occurs in the subcutaneous tissue, causing the hexamers to dissociate into dimers, and then to monomers. Historically, these regular human insulin formulations require approximately 120 minutes to reach maximum plasma concentration levels. Zinc-insulin preparations, that are more quickly absorbed than regular human insulin, have been commercialised, e.g. insulin aspart and insulin lispro.
Zinc-free insulin formulations would enable faster subcutaneous absorption, but for insulins in general, the chemical and physical stability of zinc-free formulations is a challenge.
Various insulin derivatives have been suggested for different uses.
WO 1998 042749 describes zinc-free insulin crystals for pulmonary administration.
U.S. Pat. No. 6,960,561 describes zinc-free and low-zinc insulin preparations having improved stability.
WO 2007/096431 describes certain human insulin derivatives, including analogues i.a. at position A22 holding an acylated lysine residue, in position B29 holding an arginine residue, and being desB30, which derivatives are soluble at physiological pH values and have a prolonged profile of action, and intended for use as long acting insulins.
WO 2009/022013 describes certain acylated insulin analogues, including analogues i.a. at position A22 holding an acylated lysine residue, in position B29 holding an arginine residue, and being desB30, possessing higher insulin receptor binding affinities, and intended for use as long acting insulins.
WO 2009/112583 describes certain insulin analogues, including analogues at position A22 holding a lysine residue, in position B29 holding an arginine residue, and being desB30, exhibiting improved protease stability.
WO 2011/161124 describes certain acylated insulin analogues containing additional disulfide bonds for improved stability, including analogues i.a. at position A22 holding a lysine residue, in position B29 holding an arginine residue, and being desB30.
WO 2012/171994 describes certain insulin derivative comprising two or more substitutions, including analogues i.a. at position A22 holding an acylated lysine residue, in position B29 holding an arginine residue, and being desB30, for prolonged in vivo activity.
WO 2013 063572 describes ultra-concentrated rapid-acting insulin analogue formulations optionally devoid of zinc.
Moreover, acylation of peptides and proteins with albumin binding moieties have been used to prolong the duration of action of the peptides and proteins.
However, the insulin derivatives according to the present invention have not been reported, and their use as fast acting insulin derivatives for prandial use has never been suggested.